Promoter SNPs in G1/S checkpoint regulators and their impact on the susceptibility to childhood leukemia

• Published in: Blood Vol. 109; no. 2; pp. 683 - 692
• Main Authors: Healy, Jasmine, Bélanger, Hélène, Beaulieu, Patrick, Larivière, Mathieu, Labuda, Damian, Sinnett, Daniel
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-01-2007; The Americain Society of Hematology
• Subjects: Adolescent; Biological and medical sciences; Child; Child, Preschool; Cyclin-Dependent Kinase Inhibitor Proteins - genetics; Female; G1 Phase; Gene Frequency; Genetic Predisposition to Disease; Genotype; Haplotypes; Hematologic and hematopoietic diseases; Humans; Infant; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Polymorphism, Single Nucleotide; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - etiology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - etiology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Promoter Regions, Genetic - genetics; S Phase; Human; Checkpointing; Lymphopoiesis; Transcription promoter; Malignant hemopathy; Carcinogenesis; Signal transduction; Cyclin dependent kinase inhibiteur; G1 Phase; Acute lymphoblastic leukemia; S Phase; Cell cycle; Single nucleotide polymorphism; Child
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-02-003236

Mutations leading to the alteration of cell-cycle checkpoint functions are a common feature of most cancers. Because of the highly regulated nature of the cell cycle, it seems likely that variation in gene dosage of key components due to functional regulatory polymorphisms could play an important role in cancer development. Here we provide evidence of the involvement of promoter single-nucleotide polymorphisms (pSNPs) in the cyclin-dependent–kinase inhibitor genes CDKN2A, CDKN2B, CDKN1A, and CDKN1B in the etiology of childhood pre-B acute lymphoblastic leukemia (ALL). A case-control study, conducted in 240 patients with pre-B ALL and 277 healthy controls, combined with a family-based analysis using 135 parental trios, all of French-Canadian origin, were used to evaluate single-site genotypic as well as multilocus haplotypic associations for a total of 10 pSNPs. Using both study designs, we showed evidence of association between variants CDKN2A −222A, CDKN2B −593A, and CDKN1B −1608A, and an increased risk of ALL. These findings suggest that variable expression levels of cell-cycle inhibitor genes CDKN2A, CDKN2B, and CDKN1B due to regulatory polymorphisms could indeed influence the risk of childhood pre-B ALL and contribute to carcinogenesis.